Over one million patients each year are newly diagnosed with digestive diseases, such as inflammatory bowel diseases and colorectal cancer. Digestive tracts are directly accessible by endoscopy for the diagnosis and therapy. However, current imaging techniques do not provide sufficient resolution and contrast, and cell- and tissue-specific therapeutic approaches have been hampered by the lack of adequate image-guided systems. The major challenge of this project is to develop an endoscopic optical image- guided immobile-cell therapy system that can non-invasively make an in vivo diagnosis of digestive tract diseases at the microscopic level and can simultaneously perform the tissue-specific and cell-specific biological therapy. In the event that gastrointestinal stem cells are available for use, this system will also be utilized to accurately reconstitute them within the digestive tract. This project is a close collaboration between multidisciplinary teams with expertise in gastrointestinal pathology, cell engineering, and imaging. The first specific aim is to develop a novel high-resolution endomicroscopy imaging system based on optical frequency-domain imaging (OFDI) and confocal fluorescence microscopy. The system will be optimized for comprehensive imaging of the mouse colon at the cellular level. The second specific aim is to develop cell- specific and tissue-specific biological therapy system for digestive tract diseases. Prenatal fibroblast cells will be engineered to secrete cell-specific therapeutic cytokines, to express contrast agents such as cell- specific green fluorescence proteins, and to employ a suicide gene system for controlling the expression of therapeutic cytokines in the tissue. We believe that the impact of this 2-year project is significantly high, as it will have developed novel imaging techniques for the improved in vivo diagnosis, engineered an effective immobile cell line with controllable secretion of therapeutic and imaging-contrast agents, and tested the feasibility of endoscopic image-guided delivery of immobile cells (potentially stem cells) to treat intestinal inflammation associated with colorectal tumorigenesis. PUBLIC HEALTH RELEVANCE: This challenge grant is designed to develop a novel endoscopy system that can make a histological grade diagnosis of digestive tract diseases through the machine's eye and can simultaneously perform a tissue- specific and cell-specific biological treatment. We believe that the study proposed would provide not only important intervention to develop a novel therapy system for improving the lives of patients with digestive diseases but also a useful tool to further advance the basic and clinical research in the fields of mucosal biology and some digestive diseases.